ASCO 2025：关键见解和创新

ASCO 2025: Key Insights andInnovations HR+/HER2-Breast Cancer The Phase III SERENA-6 Trial SERENA-6’s novel trial design and ctDNA strategy ▪Approximately 70% of breast cancers are ER+/HER2- ▪ESR1 mutations activate estrogen receptor (ER) signaling, leading to endocrine resistance ▪ESR1 mutations are rare at diagnosis but emerge in ~40% of patients after progression onaromatase inhibitor (AI) + CDK4/6 inhibitor (CDK4/6i) ▪AstraZeneca’s camizestrant is a next-generation oral SERD that degrades both mutant andwild-type ER ▪SERENA-6 is the first Phase III trial to use ctDNA to guide pre-emptive endocrine therapyswitch ▪ctDNA can detect ESR1 mutations before radiographic progression ▪Trial design: Switch from AI to camizestrant upon ESR1 mutation detection, continuing thesame CDK4/6i ▪Aim: Prolong efficacy of first-line therapy by addressing ESR1-mediated resistance earlyprior to progression to second-line therapy Camizestrant’s efficacy and safety in SERENA-6 ▪Switching AI to camizestrant with continuation of CDK4/6i significantly improvesprogression-free survival (PFS) ▪PFS benefit was consistent across the CDK4/6i and clinically relevant subgroups ▪Camizestrant + CDK4/6i was well tolerated with a very low rate of treatment discontinuationsdue to adverse events ▪Photopsia was rare (Grade≥3 in 1%), non-disruptive to daily life, andcausedno structuraleye damage SERENA-6: Context and Competitive SERD Landscape ▪Innovative trial design:First study to pre-emptively switch therapy based on ctDNA-detectedESR1 mutations during first-line treatment ▪Paradigm validation:Could transform treatment algorithms by validating biomarker-basedtherapeutic decisions in clinical practice ▪Competitive differentiation:Distinguished from Orserdu (elacestrant) which lacks first-lineapplication and mutation-guided switching design ▪Pipeline competition:Multiple next-generation SERDs in Phase III development-giredestrant(persevERA,pionERA), palazestrant (OPERA-02), vepdegestrant (VERITAC-3) ▪Implementation challenges:Frequent ctDNA testing every 8 weeks creates cost, logisticalbarriers, and quality of life considerations for widespread adoption ▪Long term benefit unknown:Lack of OS and post-progression treatment data ▪Regulatory momentum:Breakthrough designation awarded June 2025 following positiveSERENA-6 results HER2+ Breast Cancer The Phase III DESTINY-Breast09 Trial Enhertu’s position in HER2+ breast cancer ▪Enhertu (trastuzumab deruxtecan) is AstraZeneca & Daiichi Sankyo flagship HER2-targetingantibody drug conjugate (ADC) ▪Approved in 2L (DESTINY-Breast03)&3L+ (DESTINY-Breast02) HER2+ metastatic breast cancer ▪The Phase III DESTINY-Breast09 evaluates Enhertu±Perjeta vs 1L standard-of-care regimen oftaxane, trastuzumab, and pertuzumab (THP) ▪Current 1L THP regimen supported by CLEOPATRA trial, in use >10 years ▪Limitations of THP: chemo-related toxicity, limited durability of response ▪Approximately 1/3 of patients receiving 1L treatment do not progress to 2L ▪Aim of DESTINY-Breast09: position Enhertu earlier in the treatment algorithm to improve long-termoutcomes Enhertu’s efficacy and safety in DESTINY-Breast09 ▪Enhertu demonstrated a statistically significant and clinically meaningful improvement inprogression-free survival (PFS)over THP arm (delta 13.8 months) ▪PFS benefit consistent across all pre-specified subgroups ▪Clinically meaningful improvement in PFS2 and greater objective response rates (ORR) ▪Grade 3+ adverse events occurred frequently but were comparable to control;discontinuation rates were lower ▪Deaths due to interstitial lung disease (ILD) not classified as Enhertu-treatment related DESTINY-Breast09: Implications and Competitive Positioning ▪Paradigm-shift:First therapy to surpass CLEOPATRA THP regimen in 1L HER2+ metastaticbreast cancer in over a decade→fundamentally alters competitive positioning ▪ADCfrontline emergence:Shifts ADCs from later-line salvage into first-line standard of care→displaces traditionaltaxane-based chemo ▪Raisesentry benchmark:First-mover ADC advantage in 1L→raises bar for future competitorsentering frontline space ▪Multi-line expansion:Enhertu demonstrates clinical benefit across 1L, 2L, 3L HER2+ settings→unprecedented competitive positioning in ADC space ▪Sequential uncertainty:Limited data on optimal ADC sequencing post-Enhertu→may limituniversal adoption in first-line ▪ILD concerns remain:(12.1%, 2 Grade 5 events)may influence competitive positioning vs.safer alternatives ▪Payer coverage considerations:Premium ADC pricing in first-line vs established generics→potential access barriers despite superior efficacy Prostate Cancer The Phase III PrTK03 Trial CAN-2409’s Potential in Localized Prostate Cancer ▪High unmet need in intermediate-to-high-risk localized prostate cancer (~151K US cases/year) ▪Standard-of-care (SoC): external beam radiation therapy (EBRT)±androgen deprivationtherapy (ADT), limited innovation in curative-intent ea